Leukotriene receptor antagonists (LTRA) and inhibitors of leukotriene synthesis (5-lipoxygenase inhibitor) have become available in the last decade. These leukotriene modifiers, as a class, have been shown to be effective in the treatment of chronic asthma and exercise-induced bronchio-constriction. Currently, the LTRAs are recommended as first-line preventer agents and second-line controller agents in the treatment of chronic asthma. McInnes (Arthritis Res Therapy 5(6): 288-9, 2003) published that “LTB4 antagonists are effective in reducing collagen- and cytokine-induced arthritis, and 5-LO-deficient mice exhibit reduced collagen-induced arthritis.” While Hicks et al stated in 2007 “Leukotriene B(4) (LTB(4)) is a lipid inflammatory mediator derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2 (PLA2), 5-lipoxygenase (5-LO) and leukotriene A(4) (LTA(4)) hydrolase. Several inflammatory diseases, including asthma, chronic obstructive pulmonary disease, arthritis and inflammatory bowel disease, have been associated with elevated levels of LTB(4). As a result, pharmacological strategies to modulate the synthesis of LTB(4) (inhibition of PLA2, 5-LO or LTA(4) hydrolase) or the effects of LTB(4) itself (antagonism of LTB(4) receptors) are being developed by several companies. Two G-protein-coupled receptors mediate the effects of LTB(4), namely BLT1 and BLT2. The pharmacology, expression and function of these two receptors were last reviewed by Tager and Luster in 2004. Since then, there has been an increased understanding of the function of these receptors, in particular for BLT2, the less well understood of the two receptors. Furthermore, since the last review in 1996, there have been several clinical developments in the use of BLT receptor antagonists for inflammatory diseases.
Pfizer was developing CP-195543, a leukotriene B4 (LTB4) antagonist, for the potential treatment of inflammatory conditions. In June 2006, the compound entered a phase II trial for rheumatoid arthritis (RA)
Singulaire (Montelukast®, trademark by Merck & Co) is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally. Montelukast blocks the action of leukotriene D4 on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene, and results in less inflammation.
Most diterpenoids are cyclic; two types are presented in the scheme below. The numbering of the atoms is according to the IUPAC rules (Pure Appl Chem, 71(4): 587-643, 1999; Section F). In nature the labdane type is widespread whereas the clerodane type is rather rare. Within the latter group often the methyl group (carbon 19) is lost in biosynthesis, resulting in so called nor-clerodanes.

The compounds of the invention represent a subgroup of clerodanes including the one in scheme (B), the acids at the positions 17 and 18 might form lactones with the hydroxy groups at the positions 12 and/or 6. In some cases it is possible that the double bond in ring A is hydroxylated and further derivatised as the other hydroxyl groups in positions 12 and 6 which all might be substituted preferably with a carbohydrate group as defined below. The compounds of the invention are further characterized by a saturated ring B.

Leukotriene B4 (LTB4; 5[S],12[R]-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) is a metabolite of arachidonic acid and is one of the most potent activators of granulocytes and macrophages. LTB4 binds to a specific G protein-coupled receptor (GPCR) named BLT (also called LTB4 receptor hereinafter) and activates the Gi and G16 classes of G proteins to inhibit adenylyl cyclase and activate phospholipase C. Exposure to LTB4 induces adhesion of granulocytes to endothelial cells, degranulation of the lysosomal enzymes, generation of superoxide, and transmigration of granulocytes, all important in the host defense against foreign organisms.
Overproduction of LTB 4 is involved in inflammatory diseases including psoriasis (Iversen, Skin. Pharmacol., 10:169-77, 1997), bronchial asthma (Turner, Clin. Invest. 97:381-387, 1996), rheumatoid arthritis (Griffith, Proc. Natl. Acad. Sci. USA. 92:517-521, 1995), inflammatory bowel diseases (Sharon, Gastroenterology. 86:453-460, 1984), and ischemic renal failure (Noiri, Proc. Natl. Acad. Sci. USA. 97:823-828, 2000).
Inflammation induced by carrageenan, originally described by Winter (Proc. Soc. Exp Biol Med 111: 544-7, 1962), is acute, nonimmune, well-researched, and highly reproducible. Cardinal signs of inflammation—edema, hyperalgesia, and erythema—develop immediately following subcutaneous injection, resulting from action of proinflammatory agents—bradykinin, histamine, tachykinins, complement and reactive oxygen, and nitrogen species. Such agents can be generated in situ at the site of insult or by infiltrating cells. Neutrophils readily migrate to sites of inflammation and can generate proinflammatory reactive oxygen and other species. The inflammatory response is usually quantified by increase in paw size (edema) which is maximal around 5 h postcarrageenan injection and is modulated by inhibitors of specific molecules within the inflammatory cascade.